Angioimmunoblastic T-cell lymphoma (AITL) and other ...
Transcript of Angioimmunoblastic T-cell lymphoma (AITL) and other ...
Angioimmunoblastic T-cell lymphoma (AITL) and other Follicular Helper cell (TFH)-related PTCL
Philippe Gaulard Département de Pathologie & Inserm U955
Hôpital Henri Mondor, Créteil, France
Bologna April 27-29, 2015
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From angioimmunoblastic lymphadenopathy to angioimmunoblastic T-cell lymphoma…!
1974: Description of « angioimmunoblastic lymphadenopathy with dysproteinemia »
1979: atypical T cells -! « immunoblastic T-cell lymphoma »
1980-88: Angioimmunoblastic T-cell lymphoma - clonal cytogenetic abnormalities - clonal T-cell receptor (TCR) gene rearrangements
2005-2007: cell of origin of AITL = TFH cell
2012 – …: « specific » mutational landscape (TET2, IDH2, DNMT3, RHOA,…)
REAL
WHO classification(s)
2015 – …: ? revisit its defining criteria and its border
KIEL updated
« No survival differences over1me (1992 – 2010).. »
Angioimmunoblastic T-cell lymphoma (AITL) : empiric therapies are not working…!
5 periods studied 1992-‐1998 1999-‐2001 2002-‐2004 2005-‐2007 2008-‐2010
TFH TBX 21 T-‐bet
GATA3
BCL6
FOXP3
TH1 cell -‐> IFN-‐γ Intracellular bacteria
TH2 cell -‐> IL4, IL5, IL13 Helminths
TFH cell -‐> IL21 B-‐cell help
Tregcell -‐>TGF-‐β, IL10 Regulatory funcBon
RORγ TH17 cell -‐> IL17, IL21 Extracellular bacteria, fungi
The main Th cell subsets
Naive CD4+
IL6 – TGF-‐β STAT3
STAT6
STAT4
STAT3
STAT5
Ascl2
Transcrip1on factors BCL6 MAF others
Soluble factors IL21 CXCL13
Cell surface receptors CXCR5 ICOS PD1 CD40L
ICOS
Tangye SG et al, Nature Rev Immunol 2013
TFH cells: a unique T-‐cell subset
" A specific function: interaction with B cells to provide help and allow antibody responses
" A unique transcriptional profile
" Express Bcl-6 and secrete IL-21
" CXCL13+, CXCR5high, ICOShigh, PD1high , low levels of T-bet, Gata-3, Rorγt and FoxP3
" Plasticity : Heterogeneous TFH cell subsets …
Sensi1vity
Specificity
" No single marker is 100% sensiBve, or 100% specific
" ICOS and PD1 are sensi1ve but less specific and CXCL13 and CD10 more specific but less sensi1ve
" CD10 stains only a proporBon of tumor cells
" !! Some are expressed by other subtypes of PTCL (incl ALCL-‐ICOS, PD1/CD10 MF/SS)
" A combina1on of several markers (at least 2 or 3?) to be recommanded (incl CD10)?
Criteria to postulate a TFH derivation in a given tumor
ICOS c-MAF PD1 BCL6 CXCL13 CD10
Grogg et al 2005; Dupuis et al 2006; Grogg et al 2006; Dorfman et al 2006; Krenacs et al 2006; Roncador et al 2007; Ortonne et al 2007; Xerri et al 2008; Yu et al 2009; Rodriguez-‐Justo et al 2009; MarafioF et al 2009; Dorfman et al. 2011; Bisig B Histopathol 2011; AgosFnelli C et al. Histopathol 2011, AOygalle Histopathology 2014; Ame-‐Thomas et al. Blood 2015
• Immune deficiencies (Primary, HIV)
• Autoimmune diseases (SLE, Sjogren’s Sme, RA,..)
• Lymphoid neoplasms – B-‐cell neoplasms /Hodgkin lymphoma – Lymphomas derived from TFH cells
TFH cells and human diseases
The cellular origin of AITL from follicular helper T cells (TFH)
CD5/CXCL13
de Leval et al. Blood, 2007
PD1
Bcl-6
ICOS
CD10
Angioimmunoblastic T-cell lymphoma
AITL
PTCL-F
TFH
Subset of CD4+ cutaneous T-cell
lymphomas
PTCL, NOS with TFH phenotype (« TFH-like »)
1. Described as a “dysimmune” non neoplasBc condiBon
2. DisBncBve clinical features, with immunologic abnormaliBes
3. Peculiar pathological aspects
AITL: the prototype of TFH-derived lymphoma
CD23
CD10
CD20
B-blasts (often EBV+)
EBER
FDC expansion
CD4+ αβT cells (TFH), often CD10+
The paradigm of AITL Pathological aspects of AITL
• Median age 57 -‐ 68 yrs • Advanced stage (III/IV) 68 – 94 % • B symptoms 52 – 86 % • Polyadenopathy 81 – 100% • Skin rash 38 – 58 % • Bulky mass 5 – 26 % • Hyperγglobulinemia 30 – 83 % • Posi1ve Coombs test 32 – 75 % • Monoclonal gammopathy 10 – 20 %
Manifesta1ons of immune dysregula1on are typical of AITL, but not universal and therefore not mandatory for the diagnosis
Reviewed in de Leval L et al, Br J Haematol 2010; Attygalle AD et al. Histopathology 2014; International T-cell Lymphoma Project, J Clin Oncol 2008; Parrens M et al. ASH proceedings 2012
AITL: clinical & biological features
Microenvironment (B-‐cells, FDC,
macrophages, vessels, eosinophils, mast cells…)
(°)
Neoplas1c TFH cells
• Variable morphology: wide spectrum+++
• Clinical presenta1on/outcome?
Importance of the microenvironment in AITL
(°) CriBcal in sustaining tumor cells (no cell lines) (°) May vary over Bme in a single case and from case to case
Iqbal et al. Blood 2010 Iqbal et al. Blood 2014
Microenvironment in AITL may have a prognostic impact
" M2 macrophages, Th17/mast cells, VEGF expression or vascular density, plasma EBV DNA (B Cells) related with prognosis (Niino et al. Pathol Intern 2010; Tripodo. Am J Pathol 2012; Zhao et al. Lab Invest 2004; Ganjoo et al. Leuk Lymphoma 2014; Au et al. Blood 2014)
" Molecular prognosticator in AITL
Th1 Th17
CXCL13
IL10 TGF-β
Ig
B
LT-β
PC
FDC
MC
- +
IL21
CD40-CD40L ICOSL-ICOS
Y Y Y
Y Y Y
LT-β
IL6
HEV
Angio poietin
TFH
VEGF
Treg - Immune deregulation,
altered immune surveillance
MAC
Eo
IL5
TARC
Gaulard P, de Leval L, Semin Cancer Biology 2014
Plasma cells, Plasmocytosis
(EBV+) LPD/ DLBCL
PTCL, NOS TFH-like
Spectrum of B-‐cell prolifera1ons is broad in AITL
1. From scacered to “increased” B blasts to DLBCL–like
2. HRS-‐like cells may be seen; should not be misdiagnosed as cHL or composite !
3. EBV posiBve (more oeen) or EBV negaBve 4. Plasma cell proliferaBon (monotypic or not) 5. Up to one third of AITL show clonal B-‐cell
populaBon : clonality analysis may be misleading!
6. Mechanisms: -‐ favoured by TFH help and decreased immune surveillance -‐ Hypermutated Ig genes with destrucBve mutaBons
Brauninger J Exp Med 2001; Lome-Maldonado Leukemia 2002; Willenbrock BJH 2007; Attygalle AJSP 2007; Nicolae AJSP 2013; Attygalle Histopathology 2014
CD20/EBER
LMP1
Angioimmunoblastic T-cell lymphoma
AITL
PTCL-F
TFH
Subset of CD4+ cutaneous T-cell
lymphomas
PTCL, NOS with TFH phenotype (« TFH-like »)
1. No recurrent translocaBon 2. Gains and losses 3. No « true » mouse model (SANROQUE, cMAF)
Oncogenic pathways…? ?
? ?
?
?
Recurrent RHOA muta1ons discovered by NGS
RHOA
GEF GAP G17V RHOA
GDP
Ac1ve
Inac1ve Loss of func1on
Dominant nega1ve
RHOA
GTP
acBn cytoskeleton, cell polarizaBon transcripBon by SRF
Palomero et al, Sakata-Yanagimoto et al, Yoo H-Y et al Nat Genetics 2014; L de Leval & P Gaulard, unpublished [RHOA mut: AITL (65%, n=76); PTCL, TFH-like (46%, n=13)]
• Up to 70% AITLs and a subset of PTCL, NOS with TFH like features • Absent in myeloid, confined to tumor cells • RHOA G17V in most cases, associa1on with TET2 muta1ons • Inducibly expressed G17V RHOA does not affect the growth or cell cycle
progression in Jurkat cells • Could also act as a TSG in ATLL (Sakata-‐Yanagimoto, 2014 EHA meeFng), gastric carcinoma
(Wang, Nat Genet 2014, Kakiuchi, Nat Genet 2014)) and Burkic lymphoma (Rhode, GCC, 2014)
TET2, DNMT3A & IDH2 are involved in DNA methylation
Adapted from Shih et al. Nat Rev Can.2012 In AITL, the 3 muta1ons are commonly associated
A peculiar model of lymphomagenesis….
Quivoron, Couronné et al. Cancer Cell 2011 Sakata-Yanagimoto et al. Nat Genetics 2014
Sakata-Yanagimoto et al. Nat Genetics 2014
TET2
Proliferative advantage
2nd hit
HSC
L
M
M
M
M
L
AML
MF
CMML
CTCF FLT3
JAK2 ASXL1
SRSF2 RAS
DNMT3A
TFH ?
LyT AITL PTCL, NOS TFH
RHOA IDH2 Others..
ICOS//IDH2 Lemonnier, Dupuy et al. unpublished
AITL" PTCL,NOS, TFH-like"
Revisit the diagnostic criteria of AITL ?
• Loss of the microenvironment ( inflammatory component, vascularity, FDC)
• Enrichment in large neoplastic cells
Follicular PTCL • Nodular growth pattern
• small/medium sized T cells
• CD4+, CD10+
• Expression of TFH markers (BCL6, CXCL13, PD1, ICOS), CD57+
• t(5;9) translocation (SYK-ITK fusion) in 20-30% of cases
• TET2 mutations
• Relationship to AITL?
de Leval L et al. AJSP 2001; Streubel B et al. Leukemia 2006; Bacon C et al. Br J Haematol 2008; Qubaja M et al. Human Pathol 2008; Huang L et al. AJSP 2009
CD3
# 23: t(5;9) positive
Nodal TFH-related PTCL Future evolutions of the WHO classification
AITL
PTCL, Follicular
PTCL, NOS TFH Phenotype
" Despite a different morphology, share a similar TFH profile, likely similar geneBc alteraBons and GEP
" RecommandaBon: extensively invesBgate any case of « PTCL, NOS » for FDC, CD10, TFH markers, EBV…..
" In the next future, may influence the clinical management & therapy
classical
Variants -‐ epitheliod -‐ pacerns 1/2/3 -‐ tumor-‐cell rich
ICOS
CD200
CTLA-4
PD1
TFH cell
BCL-6
- Microenvironment: anti-angiogenic (thalidomide, anti-VEGF/Bevacizumab), macrophages ?, B-blasts (Rituximab),… - Immunomodulatory compounds: IFNγ, cyclosporine, lenalinomide,….. - Neoplastic TFH antigens (campath, TFH antigens, cytokines (IL21, IL6), chemokines (CXCL13) - Specific pathways (PDGFRA, SYK, IDH2 inhibitors, demethylating agents…)
Nodal TFH-related PTCL : implications for therapy…?
Pathologically and biologically-oriented clinical trials…..